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2.  Indoleamine 2,3-dioxygenase inhibition attenuates lipopolysaccharide induced persistent microglial activation and depressive-like complications in fractalkine receptor (CX3CR1)-deficient mice 
Brain, behavior, and immunity  2012;31:134-142.
An impaired ability to regulate the activation of microglia by fractalkine (CX3CL1) leads to persistent neuroinflammation and behavioral alterations following lipopolysaccharide (LPS) challenge. While these responses are usually transient, LPS injection caused prolonged depressive-like behavior in fractalkine receptor deficient mice (CX3CR1−/−) that was associated with exaggerated microglial activation and induction of the tryptophan (TRP) degrading enzyme indoleamine 2,3-dioxygenase (IDO). IDO activation and subsequent generation of neuroactive kynurenine metabolites may have a pivotal role in the development of depression. Therefore, the purpose of this study was to determine the extent to which LPS-induced depressive-like behavior in CX3CR1−/− mice was dependent on IDO activation. CX3CR1−/− mice were implanted prior to LPS challenge with a slow release pellet of 1-methyl-tryptophan (1-MT), a competitive inhibitor of IDO. Here we show that the depressive-like behavior evident in CX3CR1−/− mice 72 h after LPS injection was abrogated by inhibition of IDO. LPS also decreased body weight and locomotor activity in CX3CR1−/− mice, but these effects were independent of 1-MT. Consistent with the increased metabolism of TRP by IDO, the ratio of 3-hydroxykynurenine (3-HK) to TRP was increased in the brain 72 h after LPS. Increased serotonin (5-HT) turnover was also evident in the brain. The LPS-associated increases in both 3-HK:TRP and 5-HIAA:5-HT ratios were prevented by the inhibition of IDO. Last, IDO blockade attenuated microglial activation in the prefrontal cortex and hippocampus 72 h after LPS. Collectively these data indicate that LPS-induced IDO activation contributes to persistent microglial activation and depressive-like behavior in CX3CR1−/− mice.
doi:10.1016/j.bbi.2012.08.008
PMCID: PMC3554840  PMID: 22926082
Microglia; Depression; Indoleamine 2; 3-dioxygenase; Kynurenine; fractalkine receptor; 1-methyl-tryptophan
3.  Dysregulated relationship of inflammation and oxidative stress in major depression 
Brain, behavior, and immunity  2012;31:143-152.
Chronic inflammation and oxidative stress have been implicated in the pathophysiology of Major Depressive Disorder (MDD), as well as in a number of chronic medical conditions. The aim of this study was to examine the relationship between peripheral inflammatory and oxidative stress markers in un-medicated subjects with MDD compared to non-depressed healthy controls and compared to subjects with MDD after antidepressant treatment. We examined the relationships between IL-6, IL-10, and the IL-6/IL-10 inflammatory ratio vs. F2-isoprostanes (F2-IsoP), a marker of oxidative stress, in un-medicated MDD patients (n = 20) before and after 8 weeks of open-label sertraline treatment (n = 17), compared to healthy non-depressed controls (n = 20). Among the un-medicated MDD subjects, F2-IsoP concentrations were positively correlated with IL-6 concentrations (p < 0.05) and were negatively correlated with IL-10 concentrations (p < 0.01). Accordingly, F2-IsoP concentrations were positively correlated with the ratio of IL-6/IL-10 (p < 0.01). In contrast, in the control group, there were no significant correlations between F2-IsoPs and either cytokine or their ratio. After MDD subjects were treated with sertraline for 8 weeks, F2-IsoPs were no longer significantly correlated with IL-6, IL-10 or the IL-6/IL-10 ratio. These data suggest oxidative stress and inflammatory processes are positively associated in untreated MDD. Our findings are consistent with the hypothesis that the homeostatic buffering mechanisms regulating oxidation and inflammation in healthy individuals become dysregulated in untreated MDD, and may be improved with antidepressant treatment. These findings may help explain the increased risk of comorbid medical illnesses in MDD.
doi:10.1016/j.bbi.2012.11.011
PMCID: PMC3669232  PMID: 23201587
Inflammation; Oxidation; Oxidative stress; IL-6; IL-10; F2-isoprostane; Depression; Sertraline
4.  Association of IL-12p70 and IL-6:IL-10 ratio with autism-related behaviors in 22q11.2 deletion syndrome: a preliminary report 
22q11.2 deletion syndrome (22q11DS) is a genetic disorder that conveys a significant risk for the development of social behavior disorders, including autism and schizophrenia. Also known as DiGeorge syndrome, 22q11DS is the second most common childhood genetic disorder and is characterized by an elevated risk for immune disorders, as 77% of individuals have an identifiable immune deficiency. We hypothesize that this immune dysfunction could contribute to the elevated risk of impaired social behavior seen in 22q11DS. The current study begins to elucidate these immune deficits and link them with the behavioral alterations associated with the disorder. Serum concentrations of a series of cytokines were examined, using a multiplex immunoassay, in sixteen individuals with 22q11DS and screened for autism-related behavior using the Autism Diagnostic Interview-Revised (ADI-R). This preliminary study examined correlations between specific immune proteins and each of the ADI-R algorithm scores (social, communication, and repetitive behavior). The inflammatory cytokine IL-1β, as well as the ratio between the inflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10, were correlated with social scores (r = 0.851, p = 0.004; r = 0.580, p = 0.018). In addition, the inflammatory cytokines interferon gamma and IL-12p70 were correlated with repetitive behaviors (r = 0.795, p = 0.033; r = 0.774, p = 0.002). Interestingly, IL-12 has been reported to be increased in autistic children. These data show a positive relationship between severity of autism-related behaviors and level of serum concentrations of inflammatory cytokines in individuals with 22q11DS, providing a basis for further inquiry.
doi:10.1016/j.bbi.2012.12.021
PMCID: PMC3669236  PMID: 23353117
DiGeorge syndrome; velo-cardio-facial syndrome; autism; repetitive behaviors; cytokines; immunity; inflammation; T-cell; schizophrenia
5.  Chronic mild stress eliminates the neuroprotective effect of Copaxone after CNS injury 
Brain, behavior, and immunity  2013;31:177-182.
Copolymer (Cop)-1, also known as glatiramer acetate, is an active compound of Copaxone, a drug widely used by patients with multiple sclerosis (MS). Copaxone functions in MS through two mechanisms of action, namely immunomodulation and neuroprotection. Because the immune system is suppressed or altered in depressed individuals, and since depression is often associated with neurological conditions, we were interested in examining whether the neuroprotective effect of Copaxone persists under conditions of stress-induced depressive behavior. We exposed mice to unpredictable chronic mild stress for 4 weeks and then treated them with three doses of Copaxone at 3-day intervals, with the last dose given immediately before the mice underwent a crush injury to the optic nerve. Whereas nonstressed mice exhibited a strong neuroprotective response after Copaxone treatment, this effect was completely absent in mice that underwent chronic mild stress. Interestingly, when Copaxone was combined with Prozac, the neuroprotective effect of Copaxone was regained, suggesting that chronic mild stress interferes with the neuroprotective effect of Copaxone. These results may shed a light on mechanism of action of Copaxone and lead to new combined therapies for neurodegenerative and neuroinflammatory disorders.
doi:10.1016/j.bbi.2012.12.015
PMCID: PMC3633726  PMID: 23295266
6.  Do environments in infancy moderate the association between stress and inflammation in adulthood? Initial evidence from a birth cohort in the Philippines 
Chronic inflammation is a potentially important pathway through which psychosocial stressors increase risk for cardiovascular disease. However, prior research on stress and inflammation has been conducted almost exclusively in high income, industrialized populations with low levels of infectious disease. In this study we test the hypothesis that psychosocial stressors are associated with elevated concentrations of C-reactive protein (CRP) among young adults in the Philippines (n=1,622), who have grown up in an ecological and epidemiological setting that differs substantially from that of the US. In addition, we apply a developmental, ecological perspective to consider whether microbial and nutritional environments in infancy alter patterns of association between stressors and CRP. Data come from the Cebu Longitudinal Health and Nutrition Survey, a prospective cohort study that began collecting data in 1983-84 when participants were in utero. A series of regression models indicate trends toward significant interactions between perceived stress and environmental factors in infancy, including exposure to animal feces, season of birth, and birth weight. Parental absence in childhood was a significant predictor of CRP in adulthood in interaction with exposure to animal feces in infancy. Positive associations between stressors and CRP were only evident for individuals with lower levels of microbial exposure in infancy, or lower birth weight. These results suggest that early environments influence the development of inflammatory phenotypes in ways that moderate sensitivity to psychosocial stressors in adulthood, and they underscore the value of a comparative, developmental approach to research on social environments, inflammation, and disease.
doi:10.1016/j.bbi.2012.08.010
PMCID: PMC3541465  PMID: 22960631
inflammation; high sensitivity C-reactive protein; psychoneuroimmunology; infectious disease; cardiovascular disease; developmental origins of adult disease; human ecological immunology
7.  Inflammation and Neurological Disease-Related Genes are Differentially Expressed in Depressed Patients with Mood Disorders and Correlate with Morphometric and Functional Imaging Abnormalities 
Brain, behavior, and immunity  2012;31:161-171.
Depressed patients show evidence of both proinflammatory changes and neurophysiological abnormalities such as increased amygdala reactivity and volumetric decreases of the hippocampus and ventromedial prefrontal cortex (vmPFC). However, very little is known about the relationship between inflammation and neuroimaging abnormalities in mood disorders. A whole genome expression analysis of peripheral blood mononuclear cells yielded 12 protein-coding genes (ADM, APBB3, CD160, CFD, CITED2, CTSZ, IER5, NFKBIZ, NR4A2, NUCKS1, SERTAD1, TNF) that were differentially expressed between 29 unmedicated depressed patients with a mood disorder (8 bipolar disorder, 21 major depressive disorder) and 24 healthy controls (HCs). Several of these genes have been implicated in neurological disorders and/or apoptosis. Ingenuity Pathway Analysis yielded two genes networks, one centered around TNF with NFKβ, TGFβ, and ERK as connecting hubs, and the second network indicating cell cycle and/or kinase signaling anomalies. fMRI scanning was conducted using a backward-masking task in which subjects were presented with emotionally-valenced faces. Compared with HCs, the depressed subjects displayed a greater hemodynamic response in the right amygdala, left hippocampus, and the ventromedial prefrontal cortex to masked sad versus happy faces. The mRNA levels of several genes were significantly correlated with the hemodynamic response of the amygdala, vmPFC and hippocampus to masked sad versus happy faces. Differentially-expressed transcripts were significantly correlated with thickness of the left subgenual ACC, and volume of the hippocampus and caudate. Our results raise the possibility that molecular-level immune dysfunction can be mapped onto macro-level neuroimaging abnormalities, potentially elucidating a mechanism by which inflammation leads to depression.
doi:10.1016/j.bbi.2012.10.007
PMCID: PMC3577998  PMID: 23064081
8.  Elevated Ratio of Arachidonic acid to Long-Chain Omega-3 Fatty Acids Predicts Depression Development Following Interferon-alpha Treatment: Relationship with Interleukin-6 
Cross-sectional studies have found that an elevated ratio of arachidonic acid to omega-3 fatty acid is associated with depression, and controlled intervention studies have found that decreasing this ratio through administration of omega-3 fatty acids can alleviate depressive symptoms. Additionally, arachidonic acid and omega-3 fatty acids have opposing effects on inflammatory signaling. Exogenous administration of the inflammatory cytokine interferon-alpha (IFN-α) can trigger a depressive episode in a subset of vulnerable people, though associated risk factors remain poorly understood. Using a within-subject prospective design of 138 subjects, we examined whether baseline long-chain omega-3 (docosahexaenoic acid – DHA; eicosapentaenoic acid – EPA) and omega-6 (arachidonic acid – AA; di-homo-gamma-linolenic acid – DGLA) fatty acid status was associated with depression vulnerability in hepatitis C patients treated with IFN-α. Based on the literature, we had specific a priori interest in the AA/EPA+DHA ratio. Lower baseline DHA predicted depression incidence (p=0.04), as did elevated DGLA (p=0.02) and an elevated AA/EPA+DHA ratio (p=0.007). The AA/EPA+DHA ratio predicted depression even when controlling for other critical variables such as sleep quality and race. A higher AA/EPA+DHA ratio was positively associated with both increasing Montgomery-Asperg Depression Rating Scores over time (F=4.0; p<0.05) as well as interleukin-6 levels (F=107.4; p<0.05) but not C-reactive protein. Importantly, omega-3 and omega-6 fatty acid status was not associated with sustained viral response to IFN-α treatment. These prospective data support the role of fatty acid status in depression vulnerability and indicate a potential role for omega-3 fatty acids in the prevention of inflammation-induced depression.
doi:10.1016/j.bbi.2012.08.007
PMCID: PMC3552059  PMID: 22926083
Omega-3 fatty acids; Inflammation; Arachidonic acid; Cytokine; Interleukin-6; C-reactive protein; Major depressive disorder
9.  Tyrosine Metabolism During Interferon-alpha Administration: Association with Fatigue and CSF Dopamine Concentrations 
Brain, behavior, and immunity  2012;31:153-160.
Chronic exposure to interferon (IFN)-alpha, an innate immune cytokine, produces high rates of behavioral disturbances, including depression and fatigue. These effects may be mediated by the actions of IFN-alpha on dopamine (DA) metabolism in the basal ganglia. Diminished conversion of phenylalanine (Phen) to tyrosine (Tyr), the primary amino acid precursor of DA, has been associated with inflammation, and may reflect decreased activity of the enzyme phenylalanine-hydroxylase (PAH). This study investigated the peripheral Phen/Tyr ratio in relation to cerebrospinal fluid (CSF) concentrations of DA and its metabolites in subjects treated with IFN-alpha plus ribavirin for hepatitis C and controls awaiting IFN-alpha therapy. Plasma Phen/Tyr ratios were significantly increased in IFN-alpha-treated subjects (n=25) compared to controls (n=9), and were negatively correlated with CSF DA (r=−0.59, df=15, p<0.05) and its metabolite, homovanillic acid (r=−0.67, df=15, p<0.01), and positively correlated with fatigue (r=0.44, df=23, p<0.05) in IFN-alpha-treated patients but not controls. Given the role of tetrahydrobiopterin (BH4) in the PAH conversion of Phen to Tyr, CSF concentrations of BH4 and its inactive oxidized form, dihydrobiopterin (BH2), were examined along with CSF interleukin (IL)-6 in a subset of patients. BH2 concentrations were significantly increased in IFN-alpha-treated patients (n=12) compared to controls (n=7), and decreased CSF BH4 concentrations correlated with increased CSF IL-6 (r=−0.57, df=12, p<0.05). These results indicate that IFN-alpha is associated with decreased peripheral conversion of Phen to Tyr, which in turn is associated with reduced DA in the brain as well as fatigue. These alterations may be related to oxidation of BH4 secondary to IFN-alpha-induced activation of a CNS inflammatory response.
doi:10.1016/j.bbi.2012.10.010
PMCID: PMC3578984  PMID: 23072726
interferon-alpha; dopamine synthesis; tyrosine metabolism; tetrahydrobiopterin; depression; fatigue
10.  Malaise, Melancholia and Madness: The Evolutionary Legacy of an Inflammatory Bias 
Evolutionary imperatives bred a vigorous and highly orchestrated behavioral and immune response to the microbial world that served to promote species survival and propagation. The resultant legacy is an inflammatory bias which goes largely unchecked in the modern world and is provoked not only by pathogens but also now by people. In this commentary, the authors’ contributions to the Special Issue on Inflammation and Mental Health are described, beginning with the origins of the inflammatory bias, its roots in genetic predispositions to behavioral adaptations and ultimately maladaptations, and its consequences on the developing brain. In addition, the mechanisms by which the immune system engages behavior are described including a central role for the inflammasome which may serve to link psychological stress with inflammatory and behavioral responses. Neurotransmitter systems that mediate effects of the immune system on behavior are also described along with interactions of the inflammatory bias with depression and their convergent impact on the response to stress and medical illness. Finally, translational implications are discussed including data from a clinical trial using a cytokine antagonist in depressed patients, which suggests an interaction of the inflammatory bias with other evolutionary legacies including those related to food consumption and their modern consequences of obesity and the metabolic syndrome. Taken together, the articles offer a sampling of the rich literature that has evolved regarding the role of the immune system in behavioral disorders. The grounding of this relationship in our evolutionary past may serve to inform future research both theoretically and therapeutically.
doi:10.1016/j.bbi.2013.04.009
PMCID: PMC3678371  PMID: 23639523
evolution; inflammation; cytokines; schizophrenia; autism; depression; genetics; stress; T cells; indoleamine 2,3 dioxygenase; oxidative stress; neurotransmitters
11.  Depressive Symptoms Enhance Stress-induced Inflammatory Responses 
Brain, behavior, and immunity  2012;31:172-176.
Depression is a risk factor for morbidity and mortality, and immune dysregulation may be partially responsible for this link. Proinflammatory cytokines such as interleukin 6 (IL-6) are reliable predictors of quality of life, morbidity, and many causes of mortality. The current study evaluated relationships between depressive symptoms, as assessed by the CES-D, and stress-induced inflammation. The participants, 138 healthy adults, were evaluated at rest, and after a standardized laboratory speech and mental arithmetic stressor. Compared with individuals with fewer depressive symptoms, those with more depressive symptoms produced more IL-6 in response to the stressor, as well as significantly higher levels of IL-6 both 45 minutes and 2 hours after the stressor. These findings add to our emerging understanding of the complex interactions among stress, depression, and immune dysregulation, and provide one potential pathway to explain relationships between depressive symptoms and disease.
doi:10.1016/j.bbi.2012.05.006
PMCID: PMC3518610  PMID: 22634107
12.  Transcriptional Signatures Related to Glucose and Lipid Metabolism Predict Treatment Response to the Tumor Necrosis Factor Antagonist Infliximab in Patients with Treatment-Resistant Depression 
Brain, behavior, and immunity  2013;31:205-215.
The tumor necrosis factor (TNF) antagonist infliximab was recently found to reduce depressive symptoms in patients with increased baseline inflammation as reflected by a plasma C-reactive protein concentration >5mg/L. To further explore predictors and targets of response to infliximab, differential gene expression was examined in peripheral blood mononuclear cells from infliximab responders (n=13) versus non-responders (n=14) compared to placebo at baseline and 6hr, 24hr, and 2 weeks after the first infliximab infusion. Treatment response was defined as 50% reduction in depressive symptoms at any point during the 12-week trial. One-hundred-forty-eight gene transcripts were significantly associated (1.2 fold, adjusted p≤0.01) with response to infliximab and were distinct from placebo responders. Transcripts predictive of infliximab response were associated with gluconeogenesis and cholesterol transport, and were enriched in a network regulated by hepatocyte nuclear factor (HNF)4-alpha, a transcription factor involved in gluconeogenesis and cholesterol and lipid homeostasis. Of the 148 transcripts differentially expressed at baseline, 48% were significantly regulated over time in infliximab responders, including genes related to gluconeogenesis and the HNF4-alpha network, indicating that these predictive genes were responsive to infliximab. Responders also demonstrated inhibition of genes related to apoptosis through TNF signaling at 6hr and 24hr after infusion. Transcripts down-regulated in responders 2 weeks after infliximab were related to innate immune signaling and nuclear factor-kappa B. Thus, baseline transcriptional signatures reflective of alterations in glucose and lipid metabolism predicted antidepressant response to infliximab, and infliximab response involved regulation of metabolic genes and inhibition of genes related to innate immune activation.
doi:10.1016/j.bbi.2013.04.004
PMCID: PMC3673885  PMID: 23624296
depression; infliximab; tumor necrosis factor; gene expression; gluconeogenesis
13.  Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development 
Maternal infection is a risk factor for autism spectrum disorder (ASD) and schizophrenia (SZ). Indeed, modeling this risk factor in mice through maternal immune activation (MIA) causes ASD- and SZ-like neuropathologies and behaviors in the offspring. Although MIA upregulates pro-inflammatory cytokines in the fetal brain, whether MIA leads to long-lasting changes in brain cytokines during postnatal development remains unknown. Here, we tested this possibility by measuring protein levels of 23 cytokines in the blood and three brain regions from offspring of poly(I:C)- and saline-injected mice at five postnatal ages using multiplex arrays. Most cytokines examined are present in sera and brains throughout development. MIA induces changes in the levels of many cytokines in the brains and sera of offspring in a region- and age-specific manner. These MIA-induced changes follow a few, unexpected and distinct patterns. In frontal and cingulate cortices, several, mostly pro-inflammatory, cytokines are elevated at birth, followed by decreases during periods of synaptogenesis and plasticity, and increases again in the adult. Cytokines are also altered in postnatal hippocampus, but in a pattern distinct from the other regions. The MIA-induced changes in brain cytokines do not correlate with changes in serum cytokines from the same animals. Finally, these MIA-induced cytokine changes are not accompanied by breaches in the blood-brain barrier, immune cell infiltration or increases in microglial density. Together, these data indicate that MIA leads to long-lasting, region-specific changes in brain cytokines in offspring—similar to those reported for ASD and SZ—that may alter CNS development and behavior.
doi:10.1016/j.bbi.2012.07.008
PMCID: PMC3529133  PMID: 22841693
Neuroimmunology; maternal infection; autism; schizophrenia; chemokine; serum; microglia; poly(I:C); inflammation; development
14.  Alcoholism and Inflammation: Neuroimmunology of Behavioral and Mood Disorders 
Brain, behavior, and immunity  2010;25(0 1):S13-S20.
Alcohol abuse changes behavior and can induce major mood disorders such as depression. Recent evidence in pre-clinical rodent models and humans now supports the conclusion that the innate immune system is an important physiological link between alcoholism and major depressive disorders. Deficiency of toll-like receptor 4 (TLR4), a protein that has been known to immunologists for 50 years, not only prevents lipopolysaccaride (LPS)-induced sickness behavior but recently has been demonstrated to induce resistance to chronic alcohol ingestion. Activation of the immune system by acute administration of LPS, a TLR4 agonist, as well as chronic infection with Bacille Calmette-Guérin, (BCG) causes development of depressive-like behaviors in pre-clinical rodent models. Induction of an enzyme expressed primarily in macrophages and microglia, 2,3 indoleamine dioxygenase, shunts tryptophan catabolism to form kynurenine metabolites. This enzyme is both necessary and sufficient for expression of inflammation-induced depressive-like behaviors in mice. New findings have extended these concepts to humans by showing that tryptophan catabolites of 2,3 indoleamine dioxygenase are elevated in the cerebrospinal fluid of cancer patients treated with the recombinant cytokine interferon-α. The remarkable conservation from mice to humans of the impact of inflammation on mood emphasizes the ever-expanding role for cross-talk among diverse physiological symptoms that are likely to be involved in the pathogenesis of alcohol abuse. These findings present new and challenging opportunities for scientists who are engaged in brain, behavior and immunity research.
doi:10.1016/j.bbi.2010.12.013
PMCID: PMC4068736  PMID: 21193024
Alcoholism; Pro-inflammatory Cytokines; 2,3 Indoleamine 2,3 Dioxygenase; Kynurenine; Depressive-like Behavior; Sickness Behavior
15.  Neuroimmune mechanisms of opioid-mediated conditioned immunomodulation 
Brain, behavior, and immunity  2007;22(1):89-97.
Morphine administration elicits pronounced effects on the immune system, including decreases in natural killer (NK) cell activity and lymphocyte mitogenic responsiveness. These immune alterations can become conditioned to environmental stimuli that predict morphine as a result of Pavlovian conditioning processes. Prior work in our laboratory has shown that acute morphine exposure produces dopamine-dependent reductions of NK cell activity that are mediated peripherally by neuropeptide Y Y1 receptors. The present study examined the involvement of dopamine D1 and neuropeptide Y Y1 receptors in the conditioned immunomodulatory effects of morphine. Rats received two conditioning sessions during which an injection of morphine was paired with a distinctive environment which served as the conditioned stimulus (CS). The results show that systemic administration of the D1 antagonist SCH-23390 prior to CS re-exposure prevented the conditioned suppression of splenic NK activity but did not alter conditioned decreases in mitogen-induced lymphocyte proliferation. Furthermore, bilateral microinjections of SCH-23390 directly into the nucleus accumbens shell fully blocked conditioned changes in NK activity. In a subsequent manipulation, subcutaneous injection of the Y1 receptor antagonist BIBP3226 prior to CS re-exposure was also shown to prevent conditioned effects on NK activity. Collectively, these findings provide evidence that the nucleus accumbens shell plays an important role in conditioned immunomodulation and further suggest that the conditioned and unconditioned immunomodulatory effects of opioids involve similar receptor mechanisms.
doi:10.1016/j.bbi.2007.06.009
PMCID: PMC4031923  PMID: 17689049
opioids; conditioning; immunomodulation; NK cell activity; lymphocytes; spleen; nucleus accumbens; dopamine; NPY
16.  Maintenance of a positive outlook during acute stress protects against pro-inflammatory reactivity and future depressive symptoms 
Brain, behavior, and immunity  2011;26(2):346-352.
Cognitive and affective responses to acute stress influence pro-inflammatory cytokine reactivity, and peripheral cytokines (particularly lnterleukin-1 beta (IL-1β)), can act on the brain to promote depressive symptoms. It is unknown whether acute stress-induced changes in positive affect and cognitions (POS) and pro-inflammatory reactivity predict future depressive symptoms. We examined acute stress responses among women, to determine prospective predictors of depressive symptoms. Hypotheses: 1) Stress-induced decreases in POS will be associated with stress-related increases in circulating IL-1β. 2) Acute stress-induced decreases in POS and increases in IL-1β reactivity will predict increases in depressive symptoms one year later. Thirty-five post-menopausal women were exposed to acute stress with the Trier Social Stress Task (TSST) and provided blood samples under resting conditions and 30 minutes after the conclusion of the TSST, which were assayed for IL-1β. IL-1β reactivity was quantified as post minus pre-TSST. Failure to maintain POS was quantified as the decrease in POS during the TSST. Change in depressive symptoms from the study baseline to the following year was determined. Greater acute stress-induced declines in POS were significantly associated with increased IL-1β reactivity (p≤.02), which significantly predicted increases in depressive symptoms over the following year (p<.01), controlling for age, body mass index, chronic stress, antidepressant use and baseline depressive symptoms. IL-1β reactivity was a significant mediator of the relationship between POS decline and future increases in depressive symptoms (p=.04). Difficulty maintaining positivity under stress and heightened pro-inflammatory reactivity may be markers and/or mechanisms of risk for future increases in depressive symptoms.
doi:10.1016/j.bbi.2011.10.010
PMCID: PMC4030538  PMID: 22119400
cytokine; pro-inflammatory; interleukin-1 beta; acute stress; reactivity; positive affect; depressive symptoms
17.  Absence of CCL2 is sufficient to restore hippocampal neurogenesis following cranial irradiation 
Cranial irradiation for the treatment of brain tumors causes a delayed and progressive cognitive decline that is pronounced in young patients. Dysregulation of neural stem and progenitor cells is thought to contribute to these effects by altering early childhood brain development. Earlier work has shown that irradiation creates a chronic neuroinflammatory state that severely and selectively impairs postnatal and adult neurogenesis. Here we show that irradiation induces a transient non-classical cytokine response with selective upregulation of CCL2/monocyte chemoattractant protein–1(MCP-1). Absence of CCL2 signaling in the hours after irradiation is alone sufficient to attenuate chronic microglia activation and allow the recovery of neurogenesis in the weeks following irradiation. This identifies CCL2 signaling as a potential clinical target for moderating the long-term defects in neural stem cell function following cranial radiation in children.
doi:10.1016/j.bbi.2012.09.010
PMCID: PMC3556199  PMID: 23041279
CCL2/MCP1; radiation; neurogenesis; inflammation; hippocampus
18.  Association between Posttraumatic Stress Disorder and Inflammation: A Twin Study 
Brain, behavior, and immunity  2013;30:125-132.
The association of posttraumatic stress disorder (PTSD) with cardiovascular disease risk may be mediated by inflammation. Our objective was to examine the association between PTSD and measures of inflammation and to determine whether these associations are due to shared familial or genetic factors. We measured lifetime history of PTSD using the Structured Clinical Interview for DSM-IV in 238 male middle-aged military veteran twin pairs (476 individuals), selected from the Vietnam Era Twins Registry, who were free of cardiovascular disease at baseline. We assessed inflammation using levels of high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), fibrinogen, white blood cells, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 (ICAM-1). Geometric mean levels and percent differences by PTSD were obtained from mixed-model linear regression analyses with adjustment for potential confounders. Within-pair analysis was conducted to adjust for shared family environment and genetics (monozygotic pairs). Overall, 12.4% of participants had a lifetime history of PTSD. Adjusted mean levels of hsCRP and ICAM-1 were significantly higher among those with vs. without PTSD [hsCRP: 1.75 vs. 1.31 mg/l (33% difference); ICAM-1: 319 vs. 293 ng/ml (9% difference)]. Adjustment for depression rendered the association of PTSD with hsCRP non-statistically significant. For IL-6, no consistent association was seen. Within-pair analysis produced associations that were similar in direction for all three markers but lesser in magnitude for hsCRP and IL-6. There was no evidence of interaction by zygosity. Elevated hsCRP and ICAM-1 are associated with PTSD, and these associations may be confounded by shared non-genetic, antecedent familial and environmental factors.
doi:10.1016/j.bbi.2013.01.081
PMCID: PMC3641167  PMID: 23379997
posttraumatic stress disorder; inflammation; cardiovascular disease; twins; Vietnam veterans
19.  Differential roles of TNFR1 and TNFR2 signaling in adult hippocampal neurogenesis 
Tumor necrosis factor alpha (TNFα) is a potent inhibitor of neurogenesis in vitro but here we show that TNFα signaling has both positive and negative effects on neurogenesis in vivo and is required to moderate the negative impact of cranial irradiation on hippocampal neurogenesis. In vitro, basal levels of TNFα signaling through TNFR2 are required for normal neural progenitor cell proliferation while basal signaling through TNFR1 impairs neural progenitor proliferation. TNFR1 also mediates further reductions in proliferation and elevated cell death following exposure to recombinant TNFα. In vivo, TNFR1−/− and TNFα−/− animals have elevated baseline neurogenesis in the hippocampus, whereas absence of TNFR2 decreases baseline neurogenesis. TNFα is also implicated in defects in neurogenesis that follow radiation injury but we find that loss of TNFR1 has no protective effects on neurogenesis and loss of TNFα or TNFR2 worsened the effects of radiation injury on neurogenesis. We conclude that the immunomodulatory signaling of TNFα mediated by TNFR2 is more significant to radiation injury outcome than the proinflammatory signaling mediated through TNFR1.
doi:10.1016/j.bbi.2013.01.083
PMCID: PMC3641155  PMID: 23402793
TNFα; neural stem cells; neurogenesis; hippocampus; dentate gyrus; irradiation; inflammation
20.  Central inhibition of interleukin-6 trans-signaling during peripheral infection reduced neuroinflammation and sickness in aged mice 
During systemic infection, inflammatory cytokines such as interleukin (IL)-6 are produced in excess in the brain of aged mice and induce severe behavioral deficits. However, no studies have examined how pro-inflammatory IL-6 trans-signaling is involved in the exaggerated production of IL-6 in the aged brain, nor the extent to which IL-6 trans-signaling affects other markers of neuroinflammation, adhesion molecules, and behavior. Therefore, this study investigated in aged mice the presence of IL-6 signaling subunits in microglia; the central effects of soluble gp130 (sgp130)—a natural inhibitor of the IL-6 trans-signaling pathway—on IL-6 production in microglia; and the effects of sgp130 given intracerebroventricularly (ICV) on neuroinflammation and sickness behavior caused by i.p. injection of lipopolysaccharide (LPS). Here we show that microglia isolated from aged mice have higher expression of IL-6 receptor (IL-6R) compared to microglia from adults; and the level of mRNA for ADAM17, the enzyme responsible for shedding membrane-bound IL-6R in trans-signaling, is higher in the hippocampus of aged mice compared to adults. Additionally, we show in aged mice that peripheral LPS challenge elicits a hyperactive IL-6 response in microglia, and selective blockade of trans-signaling by ICV injection of sgp130 mitigates this. The sgp130-associated inhibition of IL-6 was paralleled by amelioration of exaggerated and protracted sickness behavior in aged mice. Taken together, the results show that microglia are important regulators of the IL-6 trans-signaling response in the aged brain and sgp130 exerts an anti-inflammatory effect by inhibiting the pro-inflammatory arm of IL-6 signaling.
doi:10.1016/j.bbi.2013.01.002
PMCID: PMC3641158  PMID: 23354002
Aging; microglia; interleukin-6; trans-signaling; ADAM17; sickness behavior
21.  Glucuronic acid and the ethanol metabolite ethyl-glucuronide cause Toll-like receptor 4 activation and enhanced pain 
We have previously observed that the non-opioid morphine metabolite, morphine-3-glucuronide, enhances pain via a toll-like receptor 4 (TLR4) dependent mechanism. The present studies were undertaken to determine whether TLR4-dependent pain enhancement generalizes to other classes of glucuronide metabolites. In silico modeling predicted that glucuronic acid alone and ethyl glucuronide, a minor but long-lasting ethanol metabolite, would dock to the same MD-2 portion of the TLR4 receptor complex previously characterized as the docking site for morphine-3-glucuronide. Glucuronic acid, ethyl glucuronide and ethanol all caused an increase in TLR4-dependent reporter protein expression in a cell line transfected with TLR4 and associated co-signaling molecules. Glucuronic acid-, ethyl glucuronide-, and ethanol-induced increases in TLR4 signaling were blocked by the TLR4 antagonists LPS-RS and (+)-naloxone. Glucuronic acid and ethyl glucuronide both caused allodynia following intrathecal injection in rats, which was blocked by intrathecal co-administration of the TLR4 antagonist LPS-RS. The finding that ethyl glucuronide can cause TLR4-dependent pain could have implications for human conditions such as hangover headache and alcohol withdrawal hyperalgesia, as well as suggesting that other classes of glucuronide metabolites could have similar effects.
doi:10.1016/j.bbi.2013.01.005
PMCID: PMC3641160  PMID: 23348028
glucuronic acid; ethanol; ethyl glucuronide; TLR4; (+)-naloxone; glucoronidation; metabolite
22.  Maternal autoantibodies are associated with abnormal brain enlargement in a subgroup of children with autism spectrum disorder 
Autism spectrum disorder (ASD) is very heterogeneous and multiple subtypes and etiologies likely exist. The maternal immune system has been implicated in the pathogenesis of some forms of ASD. Previous studies have identified the presence of specific maternal IgG autoantibodies with reactivity to fetal brain proteins at 37 and 73KDa in up to 12% of mothers of children with ASD. The current study evaluates the presence of these autoantibodies in an independent cohort of mothers of 181 preschool-aged male children (131 ASD, 50 typically developing [TD] controls). We also investigated whether ASD children born to mothers with these autism-specific maternal IgG autoantibodies exhibit a distinct neural phenotype by evaluating total brain volume using structural magnetic resonance imaging (MRI). Of the 131 ASD children, 10 (7.6%) were born to mothers with the 37/73Kda IgG autoantibodies (ASD-IgG). The mothers of the remaining ASD children and all TD controls were negative for these paired autoantibodies. While both ASD groups exhibited abnormal brain enlargement that is commonly observed in this age range, the ASD-IgG group exhibited a more extreme 12.1% abnormal brain enlargement relative to the TD controls. In contrast, the remaining ASD children exhibited a smaller 4.4% abnormal brain enlargement relative to TD controls. Lobar and tissue type analyses revealed that the frontal lobe is selectively enlarged in the ASD-IgG group and that both gray and white matter are similarly affected. These results suggest that maternal autoantibodies associated with autism spectrum disorder may impact brain development leading to abnormal enlargement.
doi:10.1016/j.bbi.2013.01.084
PMCID: PMC3641177  PMID: 23395715
Autism spectrum disorder; MRI; structural neuroimaging; maternal antibody; autoantibody
23.  Sex differences in the effects of adolescent stress on adult brain inflammatory markers in rats 
Both basic and clinical research indicates that females are more susceptible to stress-related affective disorders than males. One of the mechanisms by which stress induces depression is via inflammatory signaling in the brain. Stress during adolescence, in particular, can also disrupt the activation and continued development of both the hypothalamic–pituitary–adrenal (HPA) and –gonadal (HPG) axes, both of which modulate inflammatory pathways and brain regions involved in affective behavior. Therefore, we tested the hypothesis that adolescent stress differentially alters brain inflammatory mechanisms associated with affective-like behavior into adulthood based on sex. Male and female Wistar rats underwent mixed-modality stress during adolescence (PND 37–48) and were challenged with lipopolysaccharide (LPS; 250 μg/kg, i.p.) or saline 4.5 weeks later (in adulthood). Hippocampal inflammatory marker gene expression and circulating HPA and HPG axes hormone concentrations were then determined. Despite previous studies indicating that adolescent stress induces affective-like behaviors in female rats only, this study demonstrated that adolescent stress increased hippocampal inflammatory responses to LPS in males only, suggesting that differences in neuroinflammatory signaling do not drive the divergent affective-like behaviors. The sex differences in inflammatory markers were not associated with differences in corticosterone. In females that experienced adolescent stress, LPS increased circulating estradiol. Estradiol positively correlated with hippocampal microglial gene expression in control female rats, whereas adolescent stress negated this relationship. Thus, estradiol in females may potentially protect against stress-induced increases in neuroinflammation.
doi:10.1016/j.bbi.2013.01.075
PMCID: PMC3641183  PMID: 23348027
Variable stress; Cytokines; iNOS; NF-κB; Estradiol; Progesterone; Testosterone; Microglia; Depression; Anxiety
24.  Heroin-induced Conditioned Immunomodulation Requires Expression of IL-1β in the Dorsal Hippocampus 
Opioid-associated environmental stimuli elicit robust immune-altering effects via stimulation of a neural circuitry that includes the basolateral amygdala and nucleus accumbens. These brain regions are known to have both direct and indirect connections with the hippocampus. Thus, the present study evaluated whether the dorsal hippocampus (DH), and more specifically interleukin-1 beta (IL-1β) within the DH, is necessary for the expression of heroin-induced conditioned immunomodulation. Rats received five Pavlovian pairings of systemic heroin administration (1.0 mg/kg, SC) with placement into a distinct environment (conditioned stimulus, CS). Six days after conditioning, a GABAA/B agonist cocktail or IL-1β small interfering RNA (siRNA) was microinfused into the DH to inhibit neuronal activity or IL-1β gene expression prior to CS or home cage exposure. Control animals received saline or negative control siRNA microinfusions. Furthermore, all rats received systemic administration of lipopolysaccharide (LPS) to stimulate proinflammatory nitric oxide production. CS exposure suppressed LPS-induced nitric oxide production relative to home cage exposure. Inactivation of, or IL-1β silencing in, the DH disrupted the CS-induced suppression of nitric oxide production relative to vehicle or negative control siRNA treatment. These results are the first to show a role for DH IL-1β expression in heroin-conditioned suppression of a proinflammatory immune response.
doi:10.1016/j.bbi.2013.01.076
PMCID: PMC3641184  PMID: 23357470
dorsal hippocampus; heroin; IL-1; conditioning; siRNA; nitric oxide
25.  The effect of gp120 on morphine's antinociceptive and neurophysiological actions 
Brain, behavior, and immunity  2011;25(7):1434-1443.
Recently, we have shown that morphine's analgesic activity can be attenuated by chemokines, specifically CCL5 and CXCL12. Because the HIV-1 coat protein, glycoprotein 120 (gp120), binds to the same receptors as do CCL5 and CXCL12, experiments were designed to investigate the effect of gp120 in the brain on antinociception induced by morphine in the cold-water (-3°C) tail-flick (CWT) and hot-plate (+54°C) tests. In addition, mu-opioid-receptor-mediated effects in brain periaqueductal grey (PAG) slices were examined with whole-cell patch-clamp recordings. The results showed that (1) pretreatment with gp120 itself (10, 25, 50, 100 or 133 ng, PAG) had no nociceptive effect in the CWT; (2) pretreatment with gp120 (25 or 100 ng) dose-dependently reduced antinociception induced by subcutaneous (sc) injection of morphine (3 or 6 mg/kg) or PAG injection of morphine (100 ng) in the CWT; (3) a PAG injection of gp120 (133 ng), given 30 min before sc injection of morphine (6 mg/kg), similarly reduced morphine antinociception in the hotplate test; (4) the inhibitory effect of gp120 on morphine-induced antinociception in the CWT was reversed by AMD3100, an antagonist of CXCR4; (5) pretreatment of slices with gp120 (200 pM) prevented morphine (10 μM)-induced hyperpolarization and reduction of input resistance in PAG neurons. Electrophysiology studies paralleled gp120-induced desensitization of a mu-opioid-receptor-mediated response in PAG neurons at the single-cell level. These studies are the first to demonstrate that the analgesic activity of morphine can be reduced by the presence of gp120 in the PAG and that pretreatment with AMD3100 is able to restore the analgesic effects of morphine.
doi:10.1016/j.bbi.2011.04.014
PMCID: PMC3998826  PMID: 21569838
Morphine; gp120; CXCR4; Antinociception; Electrophysiology; PAG; Rat

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